Cardiovascular disease is a major health problem throughout the world, having a particularly high incidence in the United States, where during each year approximately 1,500,000 persons suffer a heart attack, approximately 400,000 to 500,000 persons suffer a stroke, and approximately 5,600,000 persons suffer angina. In the United States, heart attack (i.e., myocardial infarction) is in fact the leading cause of death, and stroke is the third leading cause of death. Unstable angina, i.e., severe constricting pain of coronary origin that occurs in response to less exercise than usually required to induce angina, may be associated with sudden cardiac death. A great need exists for early, accurate diagnosis of cardiovascular diseases.
Heart attack, angina, and stroke are caused by stenosis, or narrowing, of arteries, which is closely related to formation of atherosclerotic plaque, or atherogenesis. Until recently, cardiovascular lesions were believed to form gradually, and acute clinical episodes were believed to occur only when the stenosis exceeds 40% of the cross-sectional area of the original blood vessel's lumen. However, improved therapeutic methods such as thrombolytic therapy during acute myocardial infarction have revealed that atherosclerotic lesions most likely to precipitate a heart attack often were not associated with a high degree of stenosis. From autopsy studies, a class of atherosclerotic plaque has been identified, termed unstable or vulnerable plaque, which is associated with acute myocardial infarction and which is particularly susceptible to rupture. A large proportion of cardiovascular disease is now believed to progress through one or more subclinical episodes in which unstable plaque is disrupted with local thrombin activation and subsequent healing. Acute myocardial infarction is now believed to result from formation of an occluding thrombus, or blood clot, at the site of a ruptured atherosclerotic plaque. Unstable angina is also believed to be associated with thrombus formation, while other forms of angina are believed to be associated with stenoses that are not associated with thrombosis. The presence of severe stenoses is now considered to be a marker for less occlusive, unstable plaque that may be prone to rupture. No means for identifying unstable plaque prior to an acute event or death now exists, since current angiographic methods can only detect plaque when the extent of occlusion approaches 50% of the blood vessel luminal cross-section.
Atherogenesis is believed to begin with an initial lesion that appears as a fatty streak on the inner surface of an artery, consisting of two to five layers of lipid filled macrophages known as foam cells. Subsequently an intermediate fibrofatty lesion forms, consisting of twenty to thirty alternating layers of foam cells together with T lymphocytes and smooth muscle cells that separate the layers. Ultimately a fibrous plaque forms, in which a fibrous cap covers a central necrotic zone that may contain lipid, cells, and necrotic debris. A region containing numerous smooth muscle cells may also lay beneath the central necrotic lesion. The fibrous cap of an atherosclerotic plaque consists of layers of smooth muscle cells surrounded by a dense connective tissue matrix containing basement membrane, collagen fibers, and proteoglycan dispersed throughout the matrix. Some fibrous caps are inherently weaker than others, and these weak fibrous caps are rupture-prone.
Currently available methods for diagnosing cardiovascular disease employ a variety of imaging technologies, including conventional x-ray imaging, computerized tomography, magnetic resonance imaging, ultrasound, and nuclear medicine imaging. Contrast agents and radiopharmaceuticals capable of accumulating at the site of a lesion are commercially available for use in imaging cardiovascular disease, for example in angiography and venography. However, angiograms do not detect or measure the degree of atherosclerosis accurately, since they do not detect plaques that cause no stenosis. A variety of radiopharmaceuticals have been used to study or detect cardiovascular disease, such as the nuclides .sup.201 TI, .sup.99m Tc, .sup.133 Xe; or the nuclide labeled metabolic agents .sup.11 C-2-deoxy-D-glucose, .sup.18 F-2-fluorodeoxy-D-glucose, [1-.sup.11 C]- and [.sup.123 I]-.beta.-methyl fatty acid analogs, .sup.13 N-ammonia; or infarct avid agents such as .sup.99m Tc-tetracycline, .sup.99m Tc-pyrophosphate, .sup.203 Hg-mercurials, .sup.67 Ga citrate, and the like. Improved imaging agents for diagnosis of cardiovascular lesions, especially for pre-acute event diagnosis of unstable atherosclerotic plaque, are needed.
Somatostatin is a tetradecapeptide that inhibits release of insulin and glucagon from the pancreas, inhibits growth hormone release from the hypothalamus, and reduces gastric secretions. A large number of somatostatin analogs have been developed for treatment of diseases such as diabetes, acromegaly, ulcers, pancreatitis and neuroendocrine tumors. Foegh (1993) Transplantation Proceedings 25, 2095-2097; Akyurek, et al. (1993) Transpl. Int. 8, 103-110;, disclose that angiopeptin, an analog of somatostatin, inhibits proliferation of smooth muscle cells at the site of induced lesions in blood vessels of animals. Wahlers, et al. (1994) Transplantation Proceedings 26, 2741-2742; and Meiser, et al. (1995) Transplantation Proceedings 27, 1931-1935 disclose clinical studies in which angiopeptin was used to treat post heart transplantation cardiovascular lesions in humans. U.S. Pat. No. 5,506,339 discloses that specific somatostatin analogs may be used to treat atherosclerosis associated with vascular grafts and restenosis following angioplasty, and U.S. Pat. No. 5,569,647 discloses that specific somatostatin analogs may be used to inhibit proliferation of vascular smooth muscle cells. The therapeutic efficacy of the somatostatin analogs of U.S. Pat. Nos. 5,506,339 and 5,569,647 is not predictive that such analogs act by accumulating at the site of atherosclerotic plaque. Many drugs are therapeutically effective yet do not specificaly localize at the anatomical site which is affected.
Somatostatin analogs have also been developed as imaging agents, in particular, as components of agents for imaging tumors. EP 607103 discloses specific radio-labeled somatostatin analogs for use as imaging agents to visualize somatostatin receptor accumulation, in particular, in somatostatin receptor positive tumors and metastases, in inflammatory or autoimmune disorders exhibiting somatostatin receptors, in tuberculosis, or in organ rejection after transplantation. WO 97/01579 discloses use of somatostatin analogs for imaging somatostatin receptor positive tissues and cells, in particular, tumors, metastases, inflammatory disorders and autoimmune disorders. Neither of these references suggests that somatostatin analogs may be employed to image atherosclerotic plaque.